Neuropathic pain syndromes commonly arise following traumatic injury to nerves and are often-times a problem associated with peripheral neuropathies such as those associated with HIV infection and diabetes, as well as post herpetic neuralgia. In cancer patients, neuropathic pain often follows compression or infiltration of nerves by tumors. The neuropathic pain syndromes are among the difficult to manage. Compelling evidence indicates that activation of NMDA/Nitric Oxide pathway contribute to the hyperalgesia and allodynia that occur following peripheral nerve injury or inflammation. However, recent work has uncovered a complexity not originally appreciated. A number of nNOS splice variants have been identified, including two lacking exon 2 and others lacking exons 9 and 10. Thus, at least four distinct molecular species of nNOS mRNA are expressed in neuronal tissue. The primary goal of this application is to study the molecular mechanism(s) of neuropathic pain, particularly as it relates to pain following peripheral nerve injury. Antisense approaches will utilized to correlate the cloned nNOS with its pharmacology. Initial studies from our laboratory demonstrate dramatic pharmacological differences between major form and the splice variant lacking exons 9 and 10 in morphine tolerance. Preliminary results indicate that these two splice variants also modulate neuropathic pain differently. Thus, they represent another target for my studies. Finally, data suggest that NMDA receptors mediated intracellular PKC translocation and NO production may be associated with development of both neurogenic/inflammatory hyperalgesia and morphine tolerance, providing yet another paradigm to examine. Throughout all these studies, the cellular and molecular processes associated with the expression morphine tolerance and neuropathic pain overlap. Addressing the basic mechanisms of these systems may provide insights into the development of new drugs and therapies.